1. health and fitness
2. disease

J Antimicrob Chemother 2010; 65 Suppl 3: iii25 – 33
doi:10.1093/jac/dkq298
Complicated urinary tract infections: practical solutions for the
treatment of multiresistant Gram-negative bacteria
Ann Pallett 1* and Kieran Hand 2
1
Department of Microbiology, Southampton University Hospitals NHS Trust, Southampton General Hospital, Tremona Road,
Southampton SO16 6YD, UK; 2Department of Pharmacy, Southampton University Hospitals NHS Trust,
Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
*Corresponding author. Tel: +44-23-8079-6767; Fax: +44-23-8070-2530; E-mail: [email protected]
Keywords: ESBL, AmpC, carbapenemase, urinary catheter, bacteriuria, fosfomycin, cefixime, cefpodoxime, co-amoxiclav, clavulanate,
clavulanic acid, nitrofurantoin, pivmecillinam
Introduction
What is a symptomatic UTI?
Urinary tract infections (UTIs) are among the most common
infectious diseases occurring in either the community or healthcare setting.1 Uncomplicated UTIs typically occur in the healthy
adult non-pregnant woman, while complicated UTIs (cUTIs)
may occur in all sexes and age groups and are frequently associated with either structural or functional urinary tract abnormalities. Examples include foreign bodies such as calculi (stones),
indwelling catheters or other drainage devices, obstruction,
immunosuppression, renal failure, renal transplantation and
pregnancy.2 UTI in the elderly is almost always complicated in
men with prostatic hypertrophy and in post-menopausal
women who may have an increased post-void residual
volume.3 The likelihood of treatment failure and serious complications, particularly the development of antimicrobial resistance,
is more common in cUTI. Although a broad range of pathogens
can cause cUTI, Escherichia coli remains the most common;
however, even this organism is becoming resistant to the
agents that are normally prescribed.4 This leads to a number
of management and therapeutic problems that will be discussed
below. Genetic susceptibility of individual patients to UTI has
been well reviewed recently and will not be discussed in this
article.2
Typical symptoms of a lower UTI include frequency and dysuria
without fever, chills or back pain whereas upper UTI usually presents with symptoms of pyelonephritis such as loin pain, flank
tenderness, fever or other signs of a systemic inflammatory
response.3 If both dysuria and frequency are present, the probability of a UTI is .90% and antibiotic treatment is indicated.5
However, as exemplified by the case report shown in Figure 1,
diagnosis of UTI can be difficult especially in the confused
elderly patient because of non-specificity and misleading symptoms and signs.6 As in this case, some patients may present with
signs of a chest infection or may have dual infection. The presence of delirium, urinary retention or incontinence, metabolic
acidosis or respiratory alkalosis may indicate a symptomatic
UTI in this group. It is recommended that a urine sample be collected before starting empirical antibiotic therapy for patients
with cUTI but in the elderly it is more difficult to collect a noncontaminated sample,7 and an in–out catheter may represent
the optimum approach to obtaining a reliable specimen.6 A dipstick can be used to test for the presence of leucocyte esterase
and nitrites as surrogate markers for bacteriuria in the noncatheterized patient, with negative tests associated with low
probability of bacteriuria—around 20% in women with minimal
# The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.
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Resistance in Gram-negative bacteria has been increasing, particularly over the last 6 years. This is mainly
due to the spread of strains producing extended-spectrum b-lactamases (ESBLs) such as CTX-M enzymes
or AmpC b-lactamases. Many of the isolates producing these enzymes are also resistant to trimethoprim,
quinolones and aminoglycosides, often due to plasmid co-expression of other resistance mechanisms.
CTX-M-producing Escherichia coli often occurs in the community and as E. coli is one of the commonest
organisms causing urinary tract infections (UTIs) the choice of agents to treat these infections is
diminishing. Novel combinations of antibiotics are being used in the community and broad-spectrum
agents such as carbapenems are being used increasingly as empirical treatment for severe infections.
Of particular concern therefore are reports in the UK of organisms that produce carbapenemases. As
resistance is becoming more widespread, prudent use of antimicrobials is imperative and, as asymptomatic bacteriuria is typically benign in the elderly, antibiotics should not be prescribed without clinical
signs of UTI. The use of antibiotics as suppressive therapy or long-term prophylaxis may no longer be
defensible.
Pallett and Hand
sign and occasionally there may be suppuration around the catheter.11 Even if there are no localizing signs, because the urine
culture is frequently positive the patient is assumed to have a
UTI. However, a prospective study using serological markers
identified only one-third of the patients with bacteriuria in a
long-term care facility as having a UTI, which suggests that
the diagnosis of UTI in this situation is that of exclusion. The
febrile episodes often settle spontaneously (Figure 2).11
A number of excellent guidelines reviewing the diagnosis and
treatment of ASB in adults are available.5,12 In essence, in the
absence of genitourinary symptoms, bacteriuria should not be
treated except in pregnancy or for surgical manipulation of the
urinary tract. Unnecessary treatment will lead to selection of
resistant organisms and puts patients at risk of adverse drug
effects including infection with Clostridium difficile. Likewise
there is good evidence that screening for ASB is not necessary
in pre-menopausal patients who are not pregnant, older patients
living in the community or long-term care facilities and patients
with spinal cord injury or indwelling catheters.
It is suggested by some groups that screening for ASB should also
be carried out prior to implant surgery, to determine the choice of
antibiotic for peri-operative prophylaxis (Figure 3). Treatment of
ASB prior to implant surgery is not recommended unless the
patient is symptomatic as this will select for resistance and will
make choice of the antibiotic agent for prophylaxis more difficult.
Case 1
An 85-year-old lady presented to casualty with fever, confusion and signs of a chest
infection. Blood cultures were taken and as the urine was dipstick positive it was
sent for culture.
She was admitted and commenced on co-amoxiclav. An Enterobacter sp. resistant to
amoxicillin, co-amoxiclav and cefalexin was cultured from the urine but the blood
cultures were negative and she improved clinically.
No further antibiotics were needed and the lady was discharged home.
Figure 1. Case report 1: uncomplicated UTI in an elderly patient.
Case 2
An 85-year-old man lives in a nursing home and has been catheterized for
incontinence. He becomes generally unwell but does not have any specific urinary
symptoms.
A specimen of urine is sent for culture and broad-spectrum antibiotics are given for a
possible chest infection or UTI. An E. coli is grown from the urine and is resistant to
all first-line antibiotics including gentamicin and nitrofurantoin and is identified as
an ESBL producer. His chest infection and clinical condition improve so antibiotic
treatment is stopped.
The elderly gentleman now becomes febrile after his catheter blocks. He is adamant
that he does not want to be admitted to hospital.
A stat dose of gentamicin is given intramuscularly followed by a course of cefixime
and co-amoxiclav and the blocked catheter is changed.
Figure 2. Case report 2: UTI in a catheterized elderly patient.
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signs or symptoms of a UTI and ,10% in symptomatic nursing
home residents.5,6 In symptomatic non-catheterized elderly
patients, a positive result is less reliable with the presence of leucocyte esterase having ,50% positive predictive value. However,
some experts consider that the detection of nitrites in the symptomatic patient should prompt initiation of treatment.6
The quantitative criterion appropriate for the microbiological
identification of significant bacteriuria is generally considered
to be at least 108 cfu/L. In some specific groups it is less: for
men ≥106 cfu/L; and for women with symptoms of UTI it is
≥105 cfu/L.5 Asymptomatic bacteriuria (ASB) is common in the
elderly, rising with age to .50% in women and .35% in men
over the age of 80 years. Other co-morbidities such as diabetes
mellitus or an indwelling catheter also contribute to increased
frequency of this condition.8 Algorithms have been developed
to optimize antimicrobial use for suspected UTI in the nursing
home, recommending that in the absence of minimal signs of
UTI, urine should not be cultured and antimicrobials should not
be prescribed.9 Indeed a call has been made by US clinicians
for a performance measure for not treating asymptomatic
bacteriuria.10
The diagnosis of cUTI is particularly difficult in patients who
have an indwelling catheter and present with a fever. Such a
patient is described in the case report shown in Figure 2. Costovertebral tenderness or angle pain may be a helpful localizing
JAC
Treatment of complicated urinary tract infection
Case 3
A 73-year-old lady was seen in the pre-assessment clinic for an elective hip
replacement. Urine was dipstick positive and sent for culture with results as follows:
>20 white blood cells per μL seen; no epithelial cells; E. coli resistant to amoxicillin,
co-amoxiclav and trimethoprim but susceptible to ciprofloxacin and nitrofurantoin
was isolated (>105 cfu/mL).
The orthopaedic surgeon prescribed ciprofloxacin. The patient was asked to go to
her general practitioner for a repeat specimen to confirm that urine was culture
negative before surgery would be undertaken.
The patient did not have any symptoms but a urine specimen was sent for culture.
E. coli was isolated again but was now only susceptible to nitrofurantoin and
gentamicin. It was identified as an ESBL producer.
As the patient did not have any symptoms, therapy was not indicated and
gentamicin was included in the prophylactic cover for the hip surgery.
The patient is given a 1 week course of cefixime with co-amoxiclav and the
symptoms settle.
Figure 3. Case report 3: patient with asymptomatic bacteriuria.
Antibiotic-resistant organisms that cause cUTI include Grampositive cocci such as methicillin-resistant Staphylococcus aureus
(MRSA), methicillin-resistant coagulase-negative staphylococci
(MRCoNS), vancomycin-resistant enterococci (VRE) and Gramnegative organisms particularly those species that produce
AmpC enzymes or extended-spectrum b-lactamases (ESBLs).
Urea-splitting organisms such as Proteus spp., Morganella morganii
and Providencia stuartii are often found in patients with indwelling devices. Pseudomonas spp. with their intrinsic resistance
are also problematic.11 Candida species are frequently found as
a colonizing organism and account for ,5% of cUTIs. There
are only isolated reports of other fungi causing cUTI.7
In the past few years the number of cUTIs due to resistant
Gram-negative bacteria has risen, mainly due to the spread of
ESBL-producing bacteria and these are causing a number of
management problems. Before 2003 most ESBLs seen were in
Klebsiella spp. and were mutants of TEM and SHV penicillinases.
They occurred mainly in specialist units and were often hospital
acquired.13 Recently there has been a growing problem of CTX-M
ESBLs in E. coli as well as Klebsiella and many occur in the community. Prior antibiotic therapy with agents such as cephalosporins or previous international travel are recognized risk factors for
the acquisition of these organisms.14,15 Most producers are
resistant to a wide range of cephalosporins and penicillins including piperacillin/tazobactam and many are also resistant to
non-b-lactam agents such as fluoroquinolones, trimethoprim
and gentamicin due to other co-expressed resistance mechanisms.16 CTX-M-producing E. coli are often pathogenic and a
high proportion of infections result in bacteraemia with resultant
mortality.17
Other resistant urinary bacteria include Enterobacter cloacae
that express a chromosomal AmpC b-lactamase. This enzyme
is inducible on exposure to b-lactams such as cephalosporins.
Plasmid-mediated AmpC b-lactamase in bacteria such as
Klebsiella spp. and E. coli can also confer a wide range of resistance to penicillins and most cephalosporins apart from the
fourth-generation agents cefepime and cefpirome (neither of
which is available currently in the UK). These enzymes are resistant to inhibition by clavulanic acid.18 Some of these bacteria
remain susceptible to trimethoprim and the quinolones.
The oral options available for the treatment of cUTI caused by
ESBL or AmpC-producing bacteria are limited, particularly if susceptibility testing indicates concurrent resistance to trimethoprim and quinolones.19 Most organisms remain susceptible to
nitrofurantoin; however, this agent is licensed for lower UTIs
only and the authors’ personal experience has shown that resistance may develop on treatment. One alternative is an agent
used more widely in the rest of Europe—fosfomycin. Fosfomycin
is approved by the Food and Drug Administration in the United
States for treatment of uncomplicated lower UTI and single-dose
therapy (3 g oral powder) was found to be equivalent to a 7 day
course of norfloxacin in a randomized open-label study.20 For
treatment of cUTI, dose regimens of 3 g every 2 –3 days for up
to 21 days have been used but due to limited systemic absorption, fosfomycin should not be used for pyelonephritis or severe
urinary sepsis. Fosfomycin is licensed in the UK but a licensed formulation is not currently marketed. Supplies are available from
pharmaceutical importers but a delay of 24 –48 h for a community pharmacy to obtain stock limits the usefulness of this agent
in a primary care setting.
Failures have been reported when pivmecillinam has been
used alone to treat infections caused by ESBL-producing organisms and in vitro studies have shown significantly raised MICs
at a higher inoculum of 106 cfu/spot.21,22 However, there is evidence that the addition of clavulanic acid results in a decrease
in MIC bringing it down from an intermediate/resistant range
to within the susceptible range (the modal value was reduced
from 8 –16 to 0.03–0.06 mg/L).21 A combination of agents
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The patient was transferred to a rest home for rehabilitation but a few days later she
developed urinary symptoms. The ESBL-producing E. coli was cultured again from
her urine.
iii28
clavulanic acid inhibits ESBLs and
CFM, CPD and PMEC are more
stable than AMX to other
co-expressed b-lactamases
q8h, every 8 h; q12h, every 12 h; AMC, amoxicillin/clavulanate; AMX, amoxicillin; CFM, cefixime; CPD, cefpodoxime; NIT, nitrofurantoin; PMEC, pivmecillinam.
Clavulanic acid can induce AmpC enzymes e.g. in
Enterobacter spp. possibly negating the effect
of inhibiting the ESBL. These are rarer in
community-use as directed therapy for nonAmpC producers.
high risk for selecting for superadded infections
such as C. difficile and Candida spp.
penicillin allergy
concurrent or recent
infection with
C. difficile
salvage therapy for infection with
resistant ESBL-producing
organisms when NIT not effective
or not tolerated
uncomplicated UTI due to
resistant ESBL-producing
organism not requiring
hospital admission
CFM 200 mg oral q12h
OR
CPD 100– 200 mg oral q12h
OR
PMEC 400 mg oral q8h
PLUS
Clavulanic acid in the form of
AMC 375 mg q8h
Side effects/disadvantages
Contraindications
Key advantages
Place in therapy
Treatment regimen
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containing clavulanic acid (for example co-amoxiclav) with other
readily available extended-spectrum oral antibiotics that resist
hydrolysis by common b-lactamases, such as pivmecillinam,
cefixime or cefpodoxime (Figure 3), has been used to treat
UTIs caused by CTX-M ESBL-producing E. coli.23 These combinations are unlicensed and reports of such use in the literature
are rare. They are not effective against AmpC-producing Enterobacteriaceae as the clavulanate induces the production of AmpC
enzymes, which attack the cephalosporin. Combinations of cefepime or cefpirome (both are in intravenous form only and not
available in the UK) with clavulanate could be considered,
as these agents are more stable to AmpC enzymes.23 In
summary, these combinations should not be used as empirical
therapy but could be considered once the organism and type
of resistance are known. Table 1 summarizes some of the important properties of antibiotic combinations used off-licence for the
treatment of infections caused by ESBL-producing pathogens.
It may be possible to use intravenous agents that can be
given once a day such as gentamicin (also suitable for intramuscular injection) and ertapenem on an outpatient basis.24,25
Gentamicin is contraindicated in significant renal impairment,
which is more common in the elderly, and regular monitoring
of pre-dose serum concentrations is required to assess further
dosing. When infection is more severe (Figure 4) and the
patient possibly has bacteraemia, intravenous therapy should
be given. The choice of antibiotic will depend on the severity
and site of the infection and whether the susceptibility pattern
of the organism is known. A treatment strategy should be
based on the local susceptibility pattern, so where the local
pathogens remain susceptible, for instance in areas where
CTX-M ESBL-producing E. coli is predominant, gentamicin may
be used as empirical therapy—in combination with other
agents to treat a severe infection. Amikacin has been used as
an alternative where gentamicin-resistant isolates remain susceptible to it.
It is important to note that delay in adequate therapy will
lead to adverse outcomes and potentially increased mortality.26
Carbapenems, such as meropenem and imipenem, are broadspectrum agents that can be used as empirical therapy for
severe sepsis that may be caused by ESBL- or AmpC-producing
bacteria. Ertapenem and temocillin are reserved mainly for
treatment of appropriate infections of known aetiology, as they
are both inactive against Pseudomonas spp. Temocillin is also
inactive against Gram-positive bacteria and Bacteroides spp.
Carbapenemase-producing E. coli and Klebsiella pneumoniae
have been isolated but are still uncommon in the UK, although
ertapenem and temocillin resistance is slightly more
common.25,27 International travel, particularly to the Indian subcontinent, is a risk factor for the acquisition of bacteria producing
a newly described carbapenemase known as New Delhi
metallo-b-lactamase (NDM).28
Although tigecycline has activity against ESBL-producing bacteria it is unstable in the urinary tract and thus is not a first-line
antibiotic for treatment of these infections unless the source of
the organisms is known to be a different site. Tigecycline has a
large volume of distribution as evidenced by relatively low
serum levels and is therefore not recommended for urinary
tract-related bloodstream infection. It is also unreliable
against Proteus and Pseudomonas spp., which are inherently
resistant. 24,29
Table 1. Combinations of oral antibiotics that have been used specifically for the treatment of uncomplicated UTIs caused by ESBL-producing bacteria (please note: these
combinations are not licensed for use in this form and are not effective for the treatment of AmpC-producing Enterobacteriaceae)
Pallett and Hand
JAC
Treatment of complicated urinary tract infection
Case 4
A 56-year-old man takes ciprofloxacin for traveller’s diarrhoea whilst in India. On his
return home he becomes acutely unwell with fever, loin pain and signs of sepsis and
is admitted to hospital.
After taking blood cultures and sending urine to the laboratory, gentamicin and
piperacillin/tazobactam are started as per hospital guidelines. He improves clinically.
An ESBL-producing E. coli is cultured from the blood cultures and the urine specimen
and is found to be susceptible to gentamicin and carbapenems, but resistant to all β
-lactams, trimethoprim and ciprofloxacin. His antibiotics are switched to intravenous
ertapenem and he is discharged on this once-daily, administered by the district
nurse for a total of 10 days.
Figure 4. Case report 4: systemic sepsis and bacteraemia in a patient returning from foreign travel.
How long should a patient receive antibiotics
for?
The optimal length of treatment for symptomatic cUTI has not
been extensively studied. As there are many different causes of
underlying abnormality, a simple recommendation cannot be
made. Most clinical trials have evaluated 7–14 days of treatment, but a recent randomized multicentre study demonstrated
that levofloxacin for 5 days was non-inferior to ciprofloxacin for
10 days in cUTI and acute pyelonephritis.31 Ten to fourteen
days of antibiotics are usually recommended for patients with
bacteraemia, hypotension and other signs of severe sepsis,
whereas a 7 day regimen should suffice for those with a lower
UTI.3 A 3 day course is usually not sufficient and is thus not recommended for cUTI.32 Clinical improvement should occur within
24 –48 h after starting treatment. If the patient has not
responded, the choice of antibiotic should be reviewed in the
light of the culture results. They may need an urgent investigation to exclude an abscess that needs drainage. A patient
can be switched to an oral agent when they are clinically
improved providing they can tolerate it and the organism is
susceptible.
What preventative strategies can be used?
These have been well-reviewed in the Canadian Guidelines for
the management of cUTI in adults.1 Extended courses of antibiotics should only be used in specific situations such as for
men with a relapsing infection from a prostatic source when
6 –12 weeks of therapy have been given.33 They are not recommended as long-term prophylaxis for the prevention of infection in, for example patients with spinal cord lesions undergoing
intermittent catheterization, as prophylaxis will select for
antibiotic-resistant organisms.32 Rarely, a long-term course of
antimicrobials has been given as suppressive therapy to
prevent enlargement of stones that cannot be removed.34 In
this situation the benefit of giving the antibiotic must be
weighed against the likely side effects and the risk of selecting
for antibiotic-resistant organisms.
Sexually active women with recurrent UTI are recommended
to take prophylactic antibiotics at the time of intercourse and to
not use a spermicide-containing contraceptive. Results of studies
on the use of oral or vaginal oestrogen by post-menopausal
women with recurrent UTIs have been inconsistent and thus
the routine use of these agents has not been recommended.5
The use of oral lactulose however, to reduce constipation in
elderly patients, may be helpful and some studies have shown
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Intravenous therapy with a polymyxin (colistin or colistimethate sodium) has been used to treat infections due to multiresistant Gram-negative organisms. Although recent studies have
shown that it has acceptable effectiveness and fewer cases of
nephrotoxicity and neurotoxicity than previously reported, at
present its use is reserved mainly for ESBL-producing bacteria
that are also resistant to gentamicin and carbapenems.30
Table 2 summarizes the important properties of antibiotics available in the UK for the treatment of cUTI. Once the organism
has been identified and susceptibilities are known, therapy
should be de-escalated if possible to a narrow-spectrum agent.7
The main aim of therapy is to combat sepsis, relieve symptoms and prevent complications. In order to achieve a cure
and prevent re-infection or recurrence the obstruction must be
removed. Urinary devices such as indwelling catheters become
coated with a biofilm, which acts as a reservoir for organisms,
protecting them from the action of antimicrobials and host
defences. Thus the organisms are likely to cause recurrence of
infection and become more resistant to antimicrobials after
each course of treatment. If possible, urinary catheters should
be removed and a condom catheter or another form of drainage
system be used instead. The use of physician reminders to
remove unnecessary urinary catheters may help.2 If the patient
still requires a catheter, a new one should be inserted either
when collecting the specimen of urine in a patient with symptoms of a cUTI or soon after starting treatment for a symptomatic infection, so symptoms will settle in a shorter time and
increase the interval before the next relapse.11
Where a urinary tract abnormality is not apparent a diagnostic investigation should be carried out to look for other complicating factors such as an abscess. Options include diagnostic
imaging, which may include pelvic and renal ultrasound, intravenous pyelogram, CT or magnetic resonance imaging. Renal
investigations such as cystoscopy, retrograde pyelogram or urodynamic studies may be required depending on the history
given.7,11
Antibiotic
NIT: 100 mg oral q6h for
7 days minimum
Place in therapy
Key advantages
treatment of complicated and
uncomplicated lower UTI
Contraindications
widely available and extensive
clinical experience
resistance rare in E. coli although
more common in other
Enterobacteriaceae
renal impairment
(GFR,60 mL/min)
Side effects/disadvantages
nausea and vomiting (common)
peripheral neuropathy with long-term use
(rare)
no iv formulation
G6PD
inherent resistance in Proteus
spp. and Pseudomonas
spp.
FOF 3 g sachet oral once
every 3 days for
14 days for cUTI
treatment of complicated and
uncomplicated lower UTI
(unlicensed)
resistance rare even in Spain
where it is used extensively
oral capsules and iv formulation
also available
not suitable for
pyelonephritis or severe
urinary sepsis due to poor
systemic absorption
not licensed or marketed in the UK and thus
difficult to obtain urgently
headache or diarrhoea in 10% of patients
GEN 3 –5 mg/kg iv daily
in divided doses or
5 –7 mg/kg iv once
daily (consult local
guidelines)
option for once-daily outpatient
iv therapy for complicated
UTI
resistance relatively uncommon
severe renal impairment
nephrotoxicity
vestibular and auditory toxicity
risk of resistance in certain ESBL strains
serum levels required to determine safe and
effective continuing dosing
TMC 1 –2 g iv q12h
treatment of cUTI and other
infections caused by ESBLand
AmpC-producing bacteria
susceptible to this agent
good in vitro activity against
multiresistant ESBLs including
AmpC-producing bacteria
narrow spectrum
penicillin allergy
inactive against Gram-positive bacteria,
Bacteroides spp. and Pseudomonas spp.
provenance outside the
urinary tract to be established
limited clinical experience in the UK
ETP 1 g iv once daily
option for outpatient iv therapy
for cUTI caused by
susceptible ESBL-producing
bacteria
once-daily administration
history of penicillin
anaphylaxis
does not cover infections caused by
Pseudomonas spp.
more vulnerable than other carbapenems to
resistance combinations of impermeability
with an ESBL or AmpC
seizure rate attributed to ertapenem 0.2%
from clinical trials36
IPM (plus cilastatin)
500 mg–1 g iv q6h–
q8h (maximum
4 g/day)
treatment of cUTI and other
infections caused by ESBLand AmpC- producing
bacteria
broad spectrum of activity
including Enterococcus faecalis,
Pseudomonas spp. and
ESBL-producing bacteria
history of penicillin
anaphylaxis
renal failure (GFR , 5 mL/
min)
seizure risk 1.5%– 2% (more common with
higher doses, renal impairment and in
patients with a history of epilepsy)36
Cilastatin is required to inhibit
dehydropeptidase enzyme present on the
brush border of proximal renal tubular cells
that hydrolyses and inactivates IPM
MEM 500–1000 mg
iv q8h
treatment of cUTI and other
infections caused by ESBLand AmpC-producing
bacteria
relatively low seizure risk
(0.08%)37
broad spectrum of activity
including Pseudomonas spp.
and ESBL-producing bacteria
history of penicillin
anaphylaxis
increased hepatic enzymes (bilirubin and
transaminases) (.1% incidence)
somewhat less active carbapenem against
Gram-positive organisms
Pallett and Hand
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iii30
Table 2. Antibiotics commonly used to treat infections caused by resistant Gram-negative bacteria including AmpC- and ESBL-producing organisms
treatment of cUTI and other
infections caused by ESBLand AmpC-producing
bacteria
most potent agent in
carbapenem class
broad spectrum of activity
including Pseudomonas spp.
and ESBL-producing bacteria
relatively low seizure risk38
history of penicillin
anaphylaxis
headache very common
limited clinical experience in the UK
reduce dose in renal impairment (GFR, 50
mL/min)
TGC 100 mg iv loading
dose followed by
50 mg iv q12h
licensed for complicated skin
and soft tissue infections and
complicated intra-abdominal
infections only
treatment option in severe
penicillin allergy
salvage therapy for infection with
resistant ESBL-producing
organisms
extensive distribution
concentration in tissues
no dosage adjustment in renal
failure
cannot be given to children
,8 years of age due to
discolouration of teeth
limited urinary excretion of active drug
nausea very common (up to one-third of
patients)
relatively low serum concentrations—caution
in bacteraemia29
treatment option in severe
penicillin allergy
salvage therapy for infection with
resistant ESBL-producing
organisms
effective against wide range of
resistant Gram-negative
bacteria including
Acinetobacter spp.
Myasthenia gravis
CST 1 – 2 million units iv
q8h (15 000–25 000
units/kg iv q8h if
,60 kg)
cUTI and bacteraemia caused
by susceptible Gram-negative
bacteria resistant to other
agents
inherent resistance in Pseudomonas spp. and
acquired resistance in Proteus spp.
reduce dose in severe hepatic impairment
inherent resistance in Gram-positive bacteria,
anaerobes, Proteeae, Serratia spp.,
Providencia spp.
neurotoxicity (most commonly apnoea and
sensory disturbances in 7% of patients)
nephrotoxicity (8%– 20% in seriously ill
hospitalized patients); reduce dose in renal
impairment (GFR, 20 mL/min); monitor
renal function and discontinue if
nephrotoxicity occurs.
Treatment of complicated urinary tract infection
DOR 500 mg iv q8h
q6h, every 6 h; q8h, every 8 h; q12h, every 12 h; CST, colistin; DOR, doripenem; ETP, ertapenem; FOF, fosfomycin; GEN, gentamicin; GFR, glomerular filtration rate; G6PD,
glucose-6-phosphate dehydrogenase deficiency; IPM, imipenem; iv, intravenous; MEM, meropenem; NIT, nitrofurantoin; PMEC, pivmecillinam; TGC, tigecycline; TMC, temocillin.
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Pallett and Hand
that cranberry products (juice, tablets or capsules) may reduce
the frequency of recurrent UTI in women.5,8,33,35 In the future
other preventative strategies may include the development of
vaccines. The use of intentional colonization with benign organisms that are also susceptible to a wider range of antibiotics may
need to be considered.33
There is an urgent need for research into the effectiveness of
combinations of oral antibiotics in the treatment of complicated
UTI in ambulatory care and the impact on the epidemiology of
resistance. There is also an immediate requirement for increased
availability of fosfomycin in the UK.
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References
1 Nicolle L. Complicated urinary tract infection in adults. Can J Infect Dis
Med Microbiol 2005; 16: 349–60.
2 Lichtenberger P, Hooton TM. Complicated urinary tract infections. Curr
Infect Dis Rep 2008; 10: 499–504.
3 Nicolle LE. A practical guide to antimicrobial management of
complicated urinary tract infection. Drugs Aging 2001; 18: 243–54.
4 Nicolle LE. A practical guide to the management of complicated
urinary tract infection. Drugs 1997; 53: 583– 92.
5 Scottish Intercollegiate Guidelines Network. Management of suspected
bacterial urinary tract infection in adults. 2006. NHS Quality
Improvement Scotland. http://www.sign.ac.uk/guidelines/fulltext/88/
index.html (7 April 2010, date last accessed).
6 Gopal Rao G, Patel M. Urinary tract infection in hospitalized elderly
patients in the United Kingdom: the importance of making an accurate
diagnosis in the post broad-spectrum antibiotic era. J Antimicrob
Chemother 2009; 63: 5 –6.
7 Neal DE Jr. Complicated urinary tract infections. Urol Clin North Am
2008; 35: 13– 22.
8 Wagenlehner FM, Naber KG, Weidner W. Asymptomatic bacteriuria in
elderly patients: significance and implications for treatment. Drugs
Aging 2005; 22: 801– 7.
9 Loeb M, Brazil K, Lohfeld L et al. Effect of a multifaceted intervention on
number of antimicrobial prescriptions for suspected urinary tract
infections in residents of nursing homes: cluster randomised controlled
trial. BMJ 2005; 331: 669.
10 Gross PA, Patel B. Reducing antibiotic overuse: a call for a national
performance measure for not treating asymptomatic bacteriuria. Clin
Infect Dis 2007; 45: 1335 –7.
11 Nicolle LE. Catheter-related urinary tract infection. Drugs Aging 2005;
22: 627–39.
12 Nicolle LE, Bradley S, Colgan R et al. Infectious Diseases Society of
America guidelines for the diagnosis and treatment of asymptomatic
bacteriuria in adults. Clin Infect Dis 2005; 40: 643– 54.
13 Livermore D. The zeitgeist of resistance. J Antimicrob Chemother
2007; 60 Suppl 1: i59–i61.
iii32
15 Woodford N, Ward ME, Kaufmann ME et al. Community and hospital
spread of Escherichia coli producing CTX-M extended-spectrum
b-lactamases in the UK. J Antimicrob Chemother 2004; 54: 735–43.
16 Livermore DM, Canton R, Gniadkowski M et al. CTX-M: changing the
face of ESBLs in Europe. J Antimicrob Chemother 2007; 59: 165–74.
17 Tumbarello M, Sanguinetti M, Montuori E et al. Predictors of mortality
in patients with bloodstream infections caused by extended-spectrumb-lactamase-producing Enterobacteriaceae: importance of inadequate
initial antimicrobial treatment. Antimicrob Agents Chemother 2007; 51:
1987– 94.
18 Jacoby GA. AmpC b-lactamases. Clin Microbiol Rev 2009; 22: 161–82.
19 Prakash V, Lewis JS, Herrera ML et al. Oral and parenteral therapeutic
options for outpatient urinary infections caused by Enterobacteriaceae
producing CTX-M extended-spectrum b-lactamases. Antimicrob Agents
Chemother 2009; 53: 1278 –80.
20 de Jong Z, Pontonnier F, Plante P. Single-dose fosfomycin trometamol
(Monuril) versus multiple-dose norfloxacin: results of a multicenter study
in females with uncomplicated lower urinary tract infections. Urol Int
1991; 46: 344–8.
21 Thomas K, Weinbren MJ, Warner M et al. Activity of mecillinam
against ESBL producers in vitro. J Antimicrob Chemother 2006; 57: 367– 8.
22 Brenwald NP, Andrews J, Fraise AP. Activity of mecillinam against
AmpC b-lactamase-producing Escherichia coli. J Antimicrob Chemother
2006; 58: 223–4.
23 Livermore DM, Hope R, Mushtaq S et al. Orthodox and unorthodox
clavulanate combinations against extended-spectrum b-lactamase
producers. Clin Microbiol Infect 2008; 14 Suppl 1: 189–93.
24 Garau J. Other antimicrobials of interest in the era of extendedspectrum b-lactamases: fosfomycin, nitrofurantoin and tigecycline. Clin
Microbiol Infect 2008; 14 Suppl 1: 198– 202.
25 Livermore DM, Sefton AM, Scott GM. Properties and potential of
ertapenem. J Antimicrob Chemother 2003; 52: 331– 44.
26 Kumar A, Roberts D, Wood KE et al. Duration of hypotension before
initiation of effective antimicrobial therapy is the critical determinant of
survival in human septic shock. Crit Care Med 2006; 34: 1589 –96.
27 Livermore DM, Tulkens PM. Temocillin revived. J Antimicrob Chemother
2009; 63: 243–5.
28 Health Protection Agency. National Resistance Alert 3 ADDENDUM Carbapenemase-producing Enterobacteriaceae in the UK: NDM (New Delhi
Metallo-)b-lactamase: repeated importation from Indian subcontinent.
2009.
http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_
C/1195733763357 (7 April 2010, date last accessed).
29 Anthony KB, Fishman NO, Linkin DR et al. Clinical and microbiological
outcomes of serious infections with multidrug-resistant Gram-negative
organisms treated with tigecycline. Clin Infect Dis 2008; 46: 567– 70.
30 Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the
management of multidrug-resistant Gram-negative bacterial infections.
Clin Infect Dis 2005; 40: 1333– 41.
31 Peterson J, Kaul S, Khashab M et al. A double-blind, randomized
comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of
complicated urinary tract infections and acute pyelonephritis. Urology
2008; 71: 17– 22.
32 Dow G, Rao P, Harding G et al. A prospective, randomized trial of 3 or
14 days of ciprofloxacin treatment for acute urinary tract infection in
patients with spinal cord injury. Clin Infect Dis 2004; 39: 658–64.
Downloaded from http://jac.oxfordjournals.org/ by guest on September 9, 2014
This article is part of a Supplement sponsored by the BSAC.
A. P. has received funds for speaking at symposia and attending advisory boards organized on behalf of Novartis, Wyeth/Pfizer and AstraZeneca. K. H. has received funds for speaking at symposia and attending
advisory boards organized on behalf of Novartis, Wyeth/Pfizer and
Astellas.
14 Laupland KB, Church DL, Vidakovich J et al. Community-onset
extended-spectrum b-lactamase (ESBL) producing Escherichia coli:
importance of international travel. J Infect 2008; 57: 441–8.
Treatment of complicated urinary tract infection
JAC
33 Williams DH, Schaeffer AJ. Current concepts in urinary tract
infections. Minerva Urol Nephrol 2004; 56: 15 –31.
36 Zhanel GG, Wiebe R, Dilay L et al. Comparative review of the
carbapenems. Drugs 2007; 67: 1027– 52.
34 Chinn RH, Maskell R, Mead JA et al. Renal stones and urinary infection:
a study of antibiotic treatment. BMJ 1976; 2: 1411– 3.
37 Norrby SR, Gildon KM. Safety profile of meropenem: a review of nearly
5,000 patients treated with meropenem. Scand J Infect Dis 1999; 31:
3 –10.
35 McMurdo MET, Argo I, Phillips G et al. Cranberry or trimethoprim for the
prevention of recurrent urinary tract infections? A randomized controlled
trial in older women. J Antimicrob Chemother 2009; 63: 389–95.
38 Keam SJ. Doripenem: a review of its use in the treatment of bacterial
infections. Drugs 2008; 68: 2021 –57.
Downloaded from http://jac.oxfordjournals.org/ by guest on September 9, 2014
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